We are searching for mutations responsible for inherited neurological and psychiatric disorders, with a particular emphasis on bipolar affective disorder and schizophrenia. The phenotypic heterogeneity seen within these inherited disorders is likely multifactorial, that is the disease presentations are due to environmental influences as well as mutations in genes. The gene mutation can affect the biological activity of the protein by influencing the processing, compartmentalization and/or stability of the protein. In genetic disorders where a protein abnormality has been identified, molecular characterizations (such as southern analysis, dna sequencing, and polymerase chain amplification) are used to identify mutations that occur in and may be predictive of the non-neuronopathic and neuronopathic phenotypes. The molecular mechanisms leading to nervous system involvement in these disorders are also studied. The results of this research should provide a molecular basis for diagnosis and for the development of novel therapeutic strategies for these inherited disorders. Genes that may be involved in neuropsychiatric disorders (such as the neurotransmitter biosynthetic enzymes human tyrosine hydroxylase and tryptophan hydroxylase) are isolated and characterized. Using restriction length fragment polymorphisms (RFLP) and microsatellite DNA markers we are genotyping DNA from individuals in a large Old Order Amish kindred and performing linkage analysis in order to identify chromosome regions harboring genes involved in bipolar affective disorder (see Project #Z01 MH 02625-04 NS). For the interesting chromosome regions that are identified, high resolution physical maps will be developed and expressed sequences will be isolated and characterized. Human genomic DNA containing trinucleotide repeats is also being isolated and characterized with regard to flanking dna sequence and chromosome location. DNA from individuals affected with bipolar affective disorder, schizophrenia (particularly childhood onset, (see Project #MH- 02581-06 CHP), mental retardation, autism,attention deficit hyperactivity disorder(ADHD), or selected other psychiatric disorders is being examined by molecular techniques, including fluorescent in-situ hybridization (FISH), for the occurrence of chromosomal abnormalities, including deletions, chromosome rearrangements, and/or regions of trinucleotide repeat expansions, that may aid in the identification of disease genes.